Peptidoglycan recognition protein 1 (otherwise known as PGLYRP1, PGRP-S, TNFSF3-L, PGRP, TAG7 and PGRPS) is expressed in neutrophils and released upon their activation. PGLYRP1 is highly abundant in diseased tissue and has been shown to play an important role in the clearance of bacterial infections by the innate immune system. The family of PGLYRP proteins (PGLYRP1, PGLYRP2, PGLYRP3, PGLYRP4) all interact with bacterial peptidoglycans (PGNs) but there are important differences in the proteins' PGN binding sites. PGLYRP1 has an additional groove hypothesized to constitute a binding site for an unknown effector or signalling protein (J. Mol. Biol. 347:683-691 (2005)). PGLYRP1 is a highly conserved, 196 amino acid long protein consisting of a signal peptide and a peptidoglycan binding domain.
The identification of a signalling mechanism mediated by PGLYRP1 is important in order to understand and thereby manipulate the function of this protein in various infectious and inflammatory diseases.
TREM-1, likewise, has well-described effects in immune modulation but, thus far, the mechanism leading to TREM-1 mediated immune function has not been understood. TREM-1 is a receptor expressed on myeloid cells, such as monocytes, macrophages and neutrophils. It is a transmembrane protein consisting of 234 amino acids, including a single extracellular immunoglobulin domain and a short cytoplasmic tail. TREM-1 has no apparent signalling motif but, when activated, forms dimersmultimers and mediates signalling by associating with the ITAM-containing signalling adaptor protein, DAP12. Downstream signalling may include phosphorylation of Syk and Zap70. Downstream signalling may include activation of the NFAT, ELK, NK-kappaB transcription factor. When TREM-1 is activated, it triggers the release of pro-inflammatory cytokines, such as TNF-α (TNF-alpha), IL-8 and monocyte chemotactic protein-1, from myeloid cells.
TREM-1 is upregulated in patients with sepsis, rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) and increasing evidence supports the theory that TREM-1 contributes to the development and progression of inflammatory diseases. The blocking of TREM-1 signalling has furthermore been shown to have therapeutic activity in in vivo mouse models of RA and IBD.
The modeofaction of TREM-1 activation has remained elusive because the ligand that activates TREM-1 is not known in the art. Therefore, there is a need in the art for a means of identifying TREM-1's ligand. There is a need in the art for a method of identifying a molecule, such as an antibody, that is capable of reducing, blocking, or interfering with the interaction of TREM-1 with its ligand. There is a need in the art for a molecule, such as an antibody, that is capable of binding TREM-1's ligand and thus reducing, blocking, or interfering with the stimulation of TREM-1 by its ligand. There is a need in the art for a molecule, such as an antibody, that is capable of binding TREM-1's ligand. There is a need in the art for a molecule, such as an antibody, that is capable of binding TREM-1's ligand and thus blocking TREM-1 activation and signalling. There is a need in the art for a molecule, such as an antibody, that is capable of binding TREM-1's ligand and thus reducing or blocking cytokine release from a myeloid cell expressing TREM-1.
Disclosed herein is a method and assay for identifying TREM-1's ligand and molecules, such as antibodies, that are capable of binding the ligand of TREM-1. Described herein are antibodies that are capable of influencing TREM-1 activation. Thus, the antibodies disclosed herein are suitable for use as pharmaceuticals. Antibodies that bind the ligand of TREM-1 and that reduce or block the interaction of TREM-1 with its ligand may have a substantial impact upon the quality of life of individuals with chronic inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis and inflammatory bowel diseases.